Andrew Ewald, Ph.D.

Background and Summary
The Ewald Lab seeks to understand how groups of cells cooperate, compete, and interact to organize tissue architecture and function during development and disease progression. Our foundation is the understanding of normal organ architecture and development: how are they built during early development and then remodeled during adult life? Our disease focus is on breast cancer and, specifically, on elucidating the cellular strategies and molecular mechanisms driving metastasis. Metastasis is the multistep process by which cancer cells acquire the ability to leave the primary tumor, travel through the circulation, evade the immune system, and establish new tumors in distant vital organs. More than 90% of cancer deaths are attributable to metastasis across all organ sites. Unfortunately, few approved drugs specifically target the metastatic process, and current therapies are insufficiently effective for patients with metastatic cancer.

Our Conceptual and Experimental Approach
Cancer is the #2 cause of death in the United States and more than 90% of cancer deaths occur at metastatic stages. Yet, it is also understudied and incompletely understood. How can this be? Why isn’t metastasis already mechanistically understood and efficiently targeted by modern medical therapies? There are three fundamental challenges to studying metastasis: the essential processes occur deep inside the body, over a time period of months to decades, and it is an inherently complex systems problem. The experimental inaccessibility and long duration of metastasis makes it relatively inaccessible to microscopic observation or experimental manipulation, the basic tools of modern biology. The complexity arises because cells with organs live a social life- surrounded by and mutually influencing a diverse range of other cell types and responsive to the mechanical and chemical signals around them. Complexity hits twice- it makes it difficult to know where to start and also makes the field of metastasis unappealing to scientists who only engage with simple problems.

We recognized that major progress in understanding and treating metastatic cancer would require fundamentally new experimental tools and research ecosystems. We therefore developed new approaches that allowed us to culture live tumor tissue in the laboratory. We grow cancer cells in three dimensional (3D) environments customized to model specific stages in cancer progression, including tumor initiation, tumor growth, cancer invasion, entry into blood vessels, immune evasion, and growth of metastases in distant organs. Recent advances in laboratory automation and image analysis enable us to conduct these experiments at a large scale in a short time period, for example testing the effect of 1,000 drugs on metastasis initiation within a week. We combine cutting-edge microscopy, advanced genetics, next-generation bulk and single cell sequencing, and bioinformatic analysis to: understand how cells accomplish specific steps in metastasis, define the molecular tool-kit they utilize, and identify targets for new anti-metastatic drugs.

Research Ecosystem
Metastasis is a complex systems problem with key changes occurring at level of molecules, cells, tissues, organs, and whole-body physiology. Accordingly, it first requires the successful integration of diverse biological expertise that is normally siloed in different departments. Second, it requires the combination of deep knowledge of biological systems with the experimental, analytical, and computational frameworks developed in math, physics, and engineering. Third, it requires a fusion of the academic understanding of disease processes and the clinical and patient realities that cancer develops in real human beings, with sometimes hopeful and other times tragic consequences. Dr. Ewald earned his B.S. in physics at Haverford College and his Ph.D. in Biochemistry and Molecular Biophysics at Caltech, then did postdoctoral training at UCSF in epithelial biology and cancer metastasis. This multidisciplinary background enables him to assemble and lead teams of scientists, engineers, and clinicians to understand this terrible disease. To increase our impact within breast cancer and extend to additional cancer types, Dr. Ewald founded the Cancer Invasion and Metastasis Research Program (CIM) within the Sidney Kimmel Comprehensive Cancer Center (SKCCC). CIM brings together >40 faculty from the School of Medicine, Bloomberg School of Public Health, and the Whiting School of Engineering. CIM is co-led by Dr. Ewald, Dr. Ashani Weeraratna, and Dr. Phuoc Tran with the shared goal of understanding the biological processes driving metastasis and translating these insights to clinical trials to improve patient outcomes. The final critical piece of this ecosystem is active collaboration with the National Cancer Institute (NCI), with cancer patient advocates, and with research foundations, including BCRF, Twisted Pink, Hope Scarves, METAvivor, and the JKTG Foundation for Health and Policy. Our interactions with patient advocates provide inspiration and scientific direction for our research and critical funding for high risk, high reward projects. Partnership with the NCI, particularly through the CTD² and PSOC Networks, provides stable, long-term funding and facilitates collaborations with leading researchers across the country.

Areas of Current Research Focus
The Ewald Lab is organized to answer three fundamental questions:

How does breast cancer metastasis work at the cellular level? A diagnosis of metastasis is an empirical observation: breast cancer cells have succeeded in growing in a new organ. We used an integrated series of innovative experiments with 3D cell culture, animal model, and patient tumor tissue to demonstrate: that breast cancer cells express a conserved molecular “tool-kit” as they invade and enter blood vessels,  that they travel through the circulation in adherent groups or “clusters,” that cancer cells co-opt the surrounding normal fibroblasts and immune cells to help them, and that breast cancer cells establish multiclonal metastases that must again change their molecular “tool-kit” to grow in the new organ. Current efforts focus on identifying how metastasis works across the subtypes of breast cancer and on identifying molecular targets for broadly effective anti-metastatic therapies.

How does expression of specific genes enable cancer cells to accomplish distinct steps in metastasis? Modern sequencing methods have enumerated the most common oncogenes and tumor suppressors for the most frequently diagnosed types of cancer. It is much less clear how these molecular changes alter cancer cell behavior sufficiently to drive changes in tissue architecture and function and, ultimately, change patient health. To bridge this gap, we use cutting edge genetic techniques to make defined molecular changes within individual cells or across whole tissues and then conduct an integrated genomic, cell-behavioral, and signaling analysis of the resulting consequences. We use our innovative approaches to define molecular signals that: cause cancer cells to invade, drive uncontrolled cell division, regulate cancer cell adhesion, and allow cancer cells to survive the molecular stresses of travel through the body.

How do interactions between the cancer cell and its “microenvironment” affect metastasis? Breast tumors are not simply a collection of identical cancer cells- instead they contain a complex ecosystem of normal epithelial cells, genetically diverse cancer cells, immune cells, fibroblasts, and blood vessels. These cells all communicate with each other and are surrounded by and reciprocally interacting with a microenvironment rich in chemical and mechanical signals. Furthermore, the tumor microenvironment is known to change over time during cancer progression and in response to therapy. We, therefore, developed experimental tools to allow us to isolate and control specific cellular, molecular, and mechanical signals in the microenvironment and, thereby, test their influence on metastasis. These experiments have enabled us to demonstrate: that cancer invasion occurs preferentially into areas rich in fibrillar collagen I, that cancer cells collectively sense, respond to, and create microscale mechanical heterogeneity, that fibroblasts regulate the behavior and molecular state of cancer cells, and that cancer cells can co-opt the innate immune response to metastasis through cell surface receptors.

Future Directions
The Ewald Lab is composed of postdoctoral scholars, graduate students, undergraduate researchers, and specialized research staff who work in a collaborative and collegial fashion to answer fundamental questions in epithelial and cancer cell biology. Core values of the Ewald Lab include the respectful exchange of ideas, critical and open debate of emerging scientific concepts, personalized career development, promotion of a diverse scientific workforce, and fostering of an inclusive and international scientific community. We are always looking for a new philanthropic foundation, and federal partners to fund and accelerate our research.

Further Information

NIH Format Biosketch (click to download)

Video explaining how breast cancer invasion and metastasis works
https://www.youtube.com/watch?v=gezIo3p2dl8

Video explaining how to stop breast cancer metastasis.
https://www.youtube.com/watch?v=sYOoI9TWQ5M

Podcast with Dr. Bill Nelson, Director of the Sidney Kimmel Comprehensive Cancer Center
https://cancer-matters.blogs.hopkinsmedicine.org/2018/05/29/cancer-matters-with-dr-bill-nelson-cell-biology-with-dr-andrew-ewald/

Podcast with Dr. Akila Viswanathan, Director of the Department of Radiation Oncology and Molecular Radiation Sciences
https://cancer-matters.blogs.hopkinsmedicine.org/2020/01/28/on-target-akila-viswanathan-cancer-invasion-metastasis